title: β-endorphin via the delta opioid receptor is a major factor in the incubation of cocaine craving.
abstract: Cue-induced cocaine craving intensifies, or 'incubates', during the first few weeks of abstinence and persists over extended periods of time. One important factor implicated in cocaine addiction is the endogenous opioid β-endorphin. In the present study, we examined the possible involvement of β-endorphin in the incubation of cocaine craving. Rats were trained to self-administer cocaine (0.75 mg/kg, 10 days, 6 h/day), followed by either a 1-day or a 30-day period of forced abstinence. Subsequent testing for cue-induced cocaine-seeking behavior (without cocaine reinforcement) was performed. Rats exposed to the drug-associated cue on day 1 of forced abstinence demonstrated minimal cue-induced cocaine-seeking behavior concurrently with a significant increase in β-endorphin release in the nucleus accumbens (NAc). Conversely, exposure to the cue on day 30 increased cocaine seeking, while β-endorphin levels remained unchanged. Intra-NAc infusion of an anti-β-endorphin antibody (4 μg) on day 1 increased cue-induced cocaine seeking, whereas infusion of a synthetic β-endorphin peptide (100 ng) on day 30 significantly decreased cue response. Both intra-NAc infusions of the δ opioid receptor antagonist naltrindole (1 μg) on day 1 and naltrindole together with β-endorphin on day 30 increased cue-induced cocaine-seeking behavior. Intra-NAc infusion of the μ opioid receptor antagonist CTAP (30 ng and 3 μg) had no behavioral effect. Altogether, these results demonstrate a novel role for β-endorphin and the δ opioid receptor in the development of the incubation of cocaine craving.
authors.affiliation: Neuropsychopharmacology Laboratory, The Mina and Everard Goodman Faculty of Life Sciences and The Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel.
authors.forename: Yahav
authors.initials: Y
authors.lastname: Dikshtein
authors.forename: Royi
authors.initials: R
authors.lastname: Barnea
authors.forename: Noam
authors.initials: N
authors.lastname: Kronfeld
authors.forename: Elad
authors.initials: E
authors.lastname: Lax
authors.forename: Ilana
authors.initials: I
authors.lastname: Roth-Deri
authors.forename: Alexander
authors.initials: A
authors.lastname: Friedman
authors.forename: Iris
authors.initials: I
authors.lastname: Gispan
authors.forename: Einat
authors.initials: E
authors.lastname: Elharrar
authors.forename: Sarit
authors.initials: S
authors.lastname: Levy
authors.forename: Moshe
authors.initials: M
authors.lastname: Ben-Tzion
authors.forename: Gal
authors.initials: G
authors.lastname: Yadid
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D003463:Cues; D058999:Drug-Seeking Behavior / Q000187:drug effects; D008297:Male; D009714:Nucleus Accumbens / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D012646:Self Administration; D001615:beta-Endorphin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D017465:Receptors, Opioid, delta; D001615:beta-Endorphin; D003042:Cocaine